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How functional amyloids are regulated to restrict their activity is poorly understood. The cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that adopts an amyloid state key for memory persistence. Its monomer represses the translation of synaptic target mRNAs while phase separated, whereas its aggregated state acts as a translational activator. Here, we have explored the sequence-driven molecular determinants behind the functional aggregation of human CPEB3 (hCPEB3). We found that the intrinsically disordered region (IDR) of hCPEB3 encodes both an amyloidogenic and a phase separation domain, separated by a poly-A-rich region. The hCPEB3 amyloid core is composed by a hydrophobic region instead of the Q-rich stretch found in the Drosophila orthologue. The hCPEB3 phase separation domain relies on hydrophobic interactions with ionic strength dependence, and its droplet ageing process leads to a liquid-to-solid transition with the formation of a non-fibril-based hydrogel surrounded by starburst droplets. Furthermore, we demonstrate the differential behavior of the protein depending on its environment. Under physiological-like conditions, hCPEB3 can establish additional electrostatic interactions with ions, increasing the stability of its liquid droplets and driving a condensation-based amyloid pathway.

(English) Computational modeling and simulation (CM&S) provides a powerful cost- and time-efficient tool to access detailed mechanistic information of biomedical problems, which is not accessible in either clinical imaging or in vitro bench testing. This enables the efficient testing of medical devices for a wide range of design parameters and working conditions, dictated by patient-specific characteristics such as age, gender, ethnicity, or comorbidities. Furthermore, computational models can be used to simulate not only single patients or bench-test setups but also populations of virtual patients, from either clinical or synthetic databases to obtain informative statistics. These studies, known as in silico clinical trials, can be used to reduce, refine and augment both animal and bench tests. CM&S can thus reduce cost and accelerate the time-to-market of medical devices while improving their safety and efficacy before the first-in-human implantation. In this thesis, a predictive fluid-structure interaction (FSI) computational model of bioprosthetic heart valve replacements was developed to be used in supercomputing environments and applied to problems of biomedical and clinical interest. The end objective is to provide a framework to test and optimize valve prostheses. Given that transcatheter aortic valve replacements (TAVRs) are being implanted in lower-risk and younger patients, long-term effects such as leaflet thrombosis have become a critical concern for patients, doctors, and device manufacturers. This work is focused on predicting the thrombogenic risk and overall hemodynamic performance of bioprosthetic aortic valve replacements. Motivated by minimizing patient-device mismatch, the main questions of interest addressed involve evaluating the effect of multiple geometric and material parameters on prosthesis performance. Some of these parameters include aortic annulus eccentricity, the diameter of the sinotubular junction, coronary alignment, and leaflet r, (Español) El modelado y simulación computacional (CM&S por sus siglas en inglés) proporciona una poderosa herramienta para acceder a información mecanística detallada de problemas biomédicos, a la que no se puede acceder mediante imágenes clínicas o estudios in-vitro. Esto permite eficientemente evaluar el funcionamiento de dispositivos médicos en una amplio rango de parámetros de diseño y condiciones de trabajo, determinadas por las características específicas del paciente, como la edad, el sexo, el origen étnico o las comorbilidades. Además, los modelos computacionales se pueden utilizar para simular no solo pacientes individuales o configuraciones de prueba de banco, sino también poblaciones de pacientes virtuales, ya sea a partir de bases de datos clínicos o generados sintéticamente para obtener estadísticas informativas. Estos estudios, conocidos como ensayos clínicos in-silico, se pueden utilizar para reducir, refinar y aumentar las pruebas en animales y de banco. De este modo, CM&S permite reducir costos y acelerar los tiempos de comercialización de dispositivos médicos, al mismo tiempo mejorando su seguridad y eficacia antes de la primer implantación en un humano.En esta tesis, se desarrolló un modelo computacional predictivo de interacción fluido-estructura (FSI por sus siglas en inglés) de reemplazos de válvulas cardíacas bioprotésicas, diseñado para ser ejecutado eficientemente en superordenadores. Este modelo fue aplicado a problemas de interés biomédico y clínico. El objetivo final es proporcionar un marco para probar y optimizar diseños de prótesis de la válvula aórtica. Dado que los reemplazos de válvula aórtica transcatéter (TAVR por sus siglas en inglés) se están implantando en pacientes más jóvenes y de menor riesgo, los efectos a largo plazo, como la trombosis valvular, se han convertido en un problema crítico para pacientes, médicos y fabricantes de dispositivos. Este trabajo se centra en la predicción del riesgo trombogénico y el rendimiento hem, Postprint (published version)

The aim of this work was to analyze the influence of sex hormones and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy human hearts. Additionally, sex- and anatomy-dependent effects of ventricular tachycardia (VT) inducibility are presented. To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations). Additionally one model was augmented by a scar. The electrophysiology finite element model (FEM) simulations were carried out, using O’Hara-Rudy human myocyte model with sex phenotypes of Yang and Clancy. A systematic comparison between detailed vs smooth anatomies, male vs female normal hearts was carried out. The heart with a myocardial infarction was subjected to a programmed stimulus protocol to identify the effects of sex and anatomical detail on ventricular tachycardia inducibility. All female hearts presented QT-interval prolongation however the prolongation interval in comparison to the male phenotypes was anatomy-dependent and was not correlated to the size of the heart. Detailed geometries showed QRS fractionation and increased T-wave magnitude in comparison to the corresponding smoothed geometries. A variety of sustained VTs were obtained in the detailed and smoothed male geometries at different pacing locations, which provide evidence of the geometry-dependent differences regarding the prediction of the locations of reentry channels. In the female phenotype, sustained VTs were induced in both detailed and smooth geometries with RV apex pacing, however no consistent reentry channels were identified. Anatomical and physiological cardiac features play an important role defining risk in cardiac disease. These are often excluded from cardiac electrophysiology simulations. The assumption that the cardiac endocar, JA-S, FS, GH and MV are supported by the European Union’s Horizon 2020 research and innovation programme under grant agreements No 675451 (Compbiomed project phase 1) and No 823712 (CompBioMed project, phase 2) and project No 777204 (SilicoFCM project). Part of the simulation computing hours were provided by the CompBioMed project phase 1. JA-S was awarded computation time from Red Espanola de Supercomputacion (RES). (Activity IDs: FI-2018-2-0049 and BCV-2019-2-0014) JA-S is funded by a Ramon y Cajal fellowship (RYC-2017-22532), Ministerio de Ciencia e Innovacion, Spain; and by Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2017-2020 from the Ministerio de Ciencia e Innovacion y Universidades (PID2019-104356RBC41/AEI/10.13039/501100011033): meHeart ME PID2019-104356RB-C44. CB is funded by the Torres Quevedo Program (PTQ2018-010290), Ministerio de Ciencia e Innovacion, Spain. MV, GH and CB are funded by the Spanish Neotec project EXP - 00123159/SNEO-20191113 Generador de corazones virtuales. LKGM was funded by Fundacion Carolina-BBVA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study., Peer Reviewed, "Article signat per 11 autors/es: Pablo Gonzalez-Martin,Federica Sacco,Constantine Butakoff,Ruben Doste,Carlos Bederian,Lilian K. Gutierrez Espinosa de los Monteros,Guillaume Houzeaux,Paul A. Iaizzo,Tinen L. Iles,Mariano Vazquez,Jazmin Aguado-Sierra", Postprint (published version)

Impact simulations for damage resistance analysis are computationally intensive due to contact algorithms and advanced damage models. Both methods, which are the main ingredients in an impact event, require refined meshes at the contact zone to obtain accurate predictions of the contact force and damage onset and propagation through the material. This work presents the application of the partial Dirichlet–Neumann contact algorithm to simulate low-velocity impact problems on composite structures using High-Performance Computing. This algorithm is devised for parallel finite element codes running on supercomputers, and it is extended to explicit time integration schemes to solve impact problems including damage. The proposed framework is validated with a standard test for damage resistance on fiber-reinforced polymer matrix composites. Moreover, the parallel performance of the proposed algorithm has been evaluated in a mesh of 74M of elements running with 2400 processors, This work has received funding from the Clean Sky 2 Joint Undertaking (JU) under grant agreements No. 807083 and No. 945521 (SHERLOC project). The JU receives support from the European Union’s Horizon 2020 research and innovation program and the Clean Sky 2 JU members other than the Union. The authors gratefully acknowledge Hellenic Aerospace Industry for manufacturing of the coupons made of T800S/M21 material and Kirsa Muñoz and Miguel Ángel Jiménez from Element Materials Technology Seville, Peer Reviewed, Postprint (author's final draft)

Structural Preferences of the Protein hCPEB3 in the Prelude to Memory Consolidation 1213 Douglas Laurents , Daniel Ramírez De Mingo , David Pantoja Uceda , Rubén Hervás , Mariano Carrión Vázquez 1) "Rocasolano" Institute for Physical Chemistry, Madrid, Spain 2) Instituto Cajal, IC-CSIC, Madrid, Spain 3) School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China How are memories stored in the brain? Neurospecific forms of the cytoplasmic polyadenylation element binding protein (CPEB) are thought to promote memory consolidation by undergoing a disordered to functional amyloid conformational transformation at specific dendritic spines(1). This alters local mRNA translation and leads to a strengthening of particular dendritic spines(2). Whereas the structure of the Drosophila CPEB homolog has been recently elucidated(3), how amyloid formation occurs in the human homolog (hCPEB3) is still unclear. To address this question, we have characterized the partial structure and dynamics of the 426- residue disordered region in hCPEB3 by NMR spectroscopy(4). Five segments with partial ¿- helix formation, two with moderate polyproline II helix populations and a rigid hydrophobic segment were observed in the first 250 residues. Biophysical assays evince that residues 251- 426 can promote biomolecular condensateformation (5). Some evidence for interactions among the elements of partly populated ¿-helices and between the polyproline II helices with profilin were observed. Profilin binds both polyproline II helices and actin and could mediate dendritic spine specific fortification of the actincytoskeleton. These results provide a hypothetical working model for understanding hCPEB3 amyloid formation and its role in memory consolidation. 1. Si K, Linquist S, Kandel ER (2003) Cell 115: 897-891 2. Si K & Kandel ER (2016) Cold Spring Harb Perspect Biol. 8:a021774 3. Hervás R. ..et al.. Si K. (2020) Science 367: 1230-1234 4. Ramírez de Mingo D. ..et al.. Laurents

Lignocellulose is the most abundant renewable carbon source in the biosphere. However, the main bottleneck in its conversion to produce second generation biofuels is the saccharification step: the hydrolysis of lignocellulosic material into soluble fermentable sugars. Some anaerobic bacteria have developed an extracellular multi-enzyme complex called the cellulosome that efficiently degrades cellulosic substrates. Cellulosome complexes rely on enzyme-integrating scaffoldins that are large non-catalytic scaffolding proteins comprising several cohesin modules and additional functional modules that mediate the anchoring of the complex to the cell surface and the specific binding to its cellulosic substrate. It was proposed that mechanical forces may affect the cohesins positioned between the cell- and cellulose-anchoring points in the so-called connecting region. Consequently, the mechanical resistance of cohesins within the scaffoldin is of great importance, both to understand cellulosome function and as a parameter of industrial interest, to better mimic natural complexes through the use of the established designer cellulosome technology. Here we study how the mechanical stability of cohesins in a scaffoldin affects the enzymatic activity of a cellulosome. We found that when a cohesin of low mechanical stability is positioned in the connecting region of a scaffoldin, the activity of the resulting cellulosome is reduced as opposed to a cohesin of higher mechanical stability. This observation directly relates mechanical stability of the scaffoldin-borne cohesins to cellulosome activity and provides a rationale for the design of artificial cellulosomes for industrial applications, by incorporating mechanical stability as a new industrial parameter in the biotechnology toolbox.

BACKGROUND: Left ventricular assist devices (LVADs) are implantable pumps that act as a life support therapy for patients with severe heart failure. Despite improving the survival rate, LVAD therapy can carry major complications. Particularly, the flow distortion introduced by the LVAD in the left ventricle (LV) may induce thrombus formation. While previous works have used numerical models to study the impact of multiple variables in the intra-LV stagnation regions, a comprehensive validation analysis has never been executed. The main goal of this work is to present a model of the LV-LVAD system and to design and follow a verification, validation and uncertainty quantification (VVUQ) plan based on the ASME V&V40 and V&V20 standards to ensure credible predictions. METHODS: The experiment used to validate the simulation is the SDSU cardiac simulator, a bench mock-up of the cardiovascular system that allows mimicking multiple operation conditions for the heart-LVAD system. The numerical model is based on Alya, the BSC’s in-house platform for numerical modelling. Alya solves the Navier-Stokes equation with an Arbitrary Lagrangian-Eulerian (ALE) formulation in a deformable ventricle and includes pressure-driven valves, a 0D Windkessel model for the arterial output and a LVAD boundary condition modeled through a dynamic pressure-flow performance curve. The designed VVUQ plan involves: (a) a risk analysis and the associated credibility goals; (b) a verification stage to ensure correctness in the numerical solution procedure; (c) a sensitivity analysis to quantify the impact of the inputs on the four quantities of interest (QoIs) (average aortic root flow , maximum aortic root flow , average LVAD flow , and maximum LVAD flow ); (d) an uncertainty quantification using six validation experiments that include extreme operating conditions. RESULTS: Numerical code verification tests ensured correctness of the solution procedure and numerical calculation verification showed a gri, This project was funded in part by the FDA Critical Path Initiative and by an appointment to the Research Participation Program at the Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science, and Education through an interagency agreement between the U.S. Department of Energy and FDA to RAG. MV and AS acknowledge the funding from the project CompBioMed2 (H2020-EU.1.4.1.3. Grant number: 823712), SilicoFCM (H2020-EU.3.1.5. Grant number: 777204), and NEOTEC 2019 - "Generador de Corazones Virtuales" (“Ministerio de Economía y competititvidad”, EXP - 00123159 / SNEO-20191113). AS salary is partially funded by the “Ministerio de Economía y competititvidad” under the Torres Quevedo Program (grant number: PTQ2019-010528). CB salary is partially funded by the Torres Quevedo Program (grant number: PTQ2018-010290). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Peer Reviewed, Postprint (published version)

Background The life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world’s longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46–the cardiac sub-study of the NSHD. Methods We aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium. Discussion By combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR–ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age. Trial registration: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD)., Sources of funding used for staff salaries, CMR scan costs, consumables and relevant travel costs required for data collection, analysis and interpretation: British Heart Foundation special project grant (to G.C. SP/20/2/34841). This study has undergone peer-review by the funding body. Medical Research Council (Core Unit Level Funding:—MC UU 00019/1)., Peer Reviewed, "Article signat per 30 autors/es: Matthew Webber, Debbie Falconer, Mashael AlFarih, George Joy, Fiona Chan, Clare Davie, Lee Hamill Howes, Andrew Wong, Alicja Rapala, Anish Bhuva, Rhodri H. Davies, Christopher Morton, Jazmin Aguado-Sierra, Mariano Vazquez, Xuyuan Tao, Gunther Krausz, Slobodan Tanackovic, Christoph Guger, Hui Xue, Peter Kellman, Iain Pierce, Jonathan Schott, Rebecca Hardy, Nishi Chaturvedi, Yoram Rudy, James C. Moon, Pier D. Lambiase, Michele Orini, Alun D. Hughes & Gabriella Captur", Postprint (published version)

This work intends to study the effect of aortic annulus eccentricity and leaflet rigidity on the performance, thrombogenic risk and calcification risk in bioprosthetic aortic valve replacements (BAVRs). To address these questions, a two-way immersed fluid–structure interaction (FSI) computational model was implemented in a high-performance computing (HPC) multi-physics simulation software, and validated against a well-known FSI benchmark. The aortic valve bioprosthesis model is qualitatively contrasted against experimental data, showing good agreement in closed and open states. Regarding the performance of BAVRs, the model predicts that increasing eccentricities yield lower geometric orifice areas (GOAs) and higher normalized transvalvular pressure gradients (TPGs) for healthy cardiac outputs during systole, agreeing with in vitro experiments. Regions with peak values of residence time are observed to grow with eccentricity in the sinus of Valsalva, indicating an elevated risk of thrombus formation for eccentric configurations. In addition, the computational model is used to analyze the effect of varying leaflet rigidity on both performance, thrombogenic and calcification risks with applications to tissue-engineered prostheses. For more rigid leaflets it predicts an increase in systolic and diastolic TPGs, and decrease in systolic GOA, which translates to decreased valve performance. The peak shear rate and residence time regions increase with leaflet rigidity, but their volume-averaged values were not significantly affected. Peak solid stresses are also analyzed, and observed to increase with rigidity, elevating risk of valve calcification and structural failure. To the authors' knowledge this is the first computational FSI model to study the effect of eccentricity or leaflet rigidity on thrombogenic biomarkers, providing a novel tool to aid device manufacturers and clinical practitioners., This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 713673. The research leading to these results has also received funding from “la Caixa” Foundation, with fellowship ID: LCF/BQ/DI18/11660044, and has been co-funded by the project CompBioMed2 (H2020-EU.1.4.1.3. Grant No. 823712), Peer Reviewed, Postprint (published version)

[EN] Cardiovascular diseases currently have a major social and economic impact, constituting one of the leading causes of mortality and morbidity. Personalized computational models of the heart are demonstrating their usefulness both to help understand the mechanisms underlying cardiac disease, and to optimize their treatment and predict the patient's response. Within this framework, the Spanish Research Network for Cardiac Computational Modelling (VHeart-SN) has been launched. The general objective of the VHeart-SN network is the development of an integrated, modular and multiscale multiphysical computational model of the heart. This general objective is addressed through the following specific objectives: a) to integrate the different numerical methods and models taking into account the specificity of patients; b) to assist in advancing knowledge of the mechanisms associated with cardiac and vascular diseases; and c) to support the application of different personalized therapies. This article presents the current state of cardiac computational modelling and different scientific works conducted by the members of the network to gain greater understanding of the characteristics and usefulness of these models., [ES] Las enfermedades cardiovasculares tienen en la actualidad un gran impacto social y económico y constituyen una de las principales causas de mortalidad y morbilidad. Los modelos computacionales personalizados del corazón están demostrando ser útiles tanto para ayudar a comprender los mecanismos subyacentes a las patologías cardiacas como para optimizar su tratamiento prediciendo la respuesta del paciente. En este contexto, se ha puesto en marcha la Red Española de Investigación en Modelización Computacional Cardiaca (V-Heart SN). El objetivo general de V-Heart SN es el desarrollo de un modelo computacional multifísico y multiescala integrado del corazón. Este objetivo general se aborda a través de los siguientes objetivos específicos: a) integrar los diferentes modelos numéricos teniendo en cuenta la especificidad de los pacientes; b) ayudar a avanzar en el conocimiento de los mecanismos asociados a las diferentes patologías cardiacas y vasculares; y c) apoyar la aplicación de terapias personalizadas. Este artículo presenta el estado actual de la modelización computacional cardiaca y los diferentes trabajos científicos desarrollados por los miembros de la red para favorecer una mayor comprensión de las características y utilidad de los modelos.

[EN] Cardiovascular diseases currently have a major social and economic impact, constituting one of the leading causes of mortality and morbidity. Personalized computational models of the heart are demonstrating their usefulness both to help understand the mechanisms underlying cardiac disease, and to optimize their treatment and predict the patient's response. Within this framework, the Spanish Research Network for Cardiac Computational Modelling (VHeart-SN) has been launched. The general objective of the VHeart-SN network is the development of an integrated, modular and multiscale multiphysical computational model of the heart. This general objective is addressed through the following specific objectives: a) to integrate the different numerical methods and models taking into account the specificity of patients; b) to assist in advancing knowledge of the mechanisms associated with cardiac and vascular diseases; and c) to support the application of different personalized therapies. This article presents the current state of cardiac computational modelling and different scientific works conducted by the members of the network to gain greater understanding of the characteristics and usefulness of these models., [ES] Las enfermedades cardiovasculares tienen en la actualidad un gran impacto social y económico y constituyen una de las principales causas de mortalidad y morbilidad. Los modelos computacionales personalizados del corazón están demostrando ser útiles tanto para ayudar a comprender los mecanismos subyacentes a las patologías cardiacas como para optimizar su tratamiento prediciendo la respuesta del paciente. En este contexto, se ha puesto en marcha la Red Española de Investigación en Modelización Computacional Cardiaca (V-Heart SN). El objetivo general de V-Heart SN es el desarrollo de un modelo computacional multifísico y multiescala integrado del corazón. Este objetivo general se aborda a través de los siguientes objetivos específicos: a) integrar los diferentes modelos numéricos teniendo en cuenta la especificidad de los pacientes; b) ayudar a avanzar en el conocimiento de los mecanismos asociados a las diferentes patologías cardiacas y vasculares; y c) apoyar la aplicación de terapias personalizadas. Este artículo presenta el estado actual de la modelización computacional cardiaca y los diferentes trabajos científicos desarrollados por los miembros de la red para favorecer una mayor comprensión de las características y utilidad de los modelos.

Modeling complex material failure with competing mechanisms is a difficult task that often leads to mathematical and numerical challenges. This work contributes to the study of localized failure mechanisms by means of phase fields in a variational framework: in addition to the treatment of brittle and ductile fracture, done in previous work, we consider the case of shear band formation followed by ductile fracture. To achieve this, a new degradation function is introduced, which distinguishes between two successive failure mechanisms: (i) plastic strain localization and (ii) ductile fracture. Specifically, the onset of elastic damage is delayed to allow for the formation of shear bands driven by plastic deformations, thus accounting for the mechanisms that precede the coalescence of voids and microcracks into macroscopic ductile fractures. Once a critical degradation value has been reached, a phase-field model is introduced to capture the (regularized) kinematics of macroscopic cracks. To tackle the issue of potentially high computational cost, we propose a parallel implementation of the phase-field approach based on an iterative algorithm. The algorithm was implemented within the Alya system, a high performance computational mechanics code. Several examples show the capabilities of our implementation. We pay special attention to the ability to capture different failure mechanisms

The vortex induced vibrations (VIVs) of a pivoted cylinder with finite height have been numerically investigated. A mathematical model is introduced and described, and the resulting equations are numerically solved for low Reynolds number Re = 100, 200 and several combinations of the governing parameters. Results on the solid body trajectories, the maximum amplitude of the oscillations, the hydrodynamic force coefficients, the wake structure, and details on the vortex shedding near the cylinder are presented and discussed. The numerical results compare reasonably well with the canonical system of VIV of two-degrees of freedom circular cylinder in the laminar regime. Also, qualitative similarities with closely related VIV systems at larger Re suggest interesting lines of future research. Analytical approximations for limiting cases are done and an excellent agreement with the numerical results is obtained., This work was partially financially supported by the “Ministerio de Economıa y Competitividad, Secretarıa de Estado de Investigacion, Desarrollo e Innovacion,” Spain (Ref. TRA2017-88508-R). D. Pastrana acknowledges the support of the CONACyT-SENER graduate fellowship program to study abroad 278102/439162. J. C. Cajas acknowledges the financial support of UNAM through the project PAPIIT-IA106120 and the access to supercomputing resources at Miztli: LANCAD-UNAM-DGTIC-379., Peer Reviewed, Postprint (author's final draft)

Delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging requires novel and time-efficient approaches to characterize the myocardial substrate associated with ventricular arrhythmia in patients with ischemic cardiomyopathy. Using a translational approach in pigs and patients with established myocardial infarction, we tested and validated a novel 3D methodology to assess ventricular scar using custom transmural criteria and a semiautomatic approach to obtain transmural scar maps in ventricular models reconstructed from both 3D-acquired and 3D-upsampled-2D-acquired LGE-CMR images. The results showed that 3D-upsampled models from 2D LGE-CMR images provided a time-efficient alternative to 3D-acquired sequences to assess the myocardial substrate associated with ischemic cardiomyopathy. Scar assessment from 2D-LGE-CMR sequences using 3D-upsampled models was superior to conventional 2D assessment to identify scar sizes associated with the cycle length of spontaneous ventricular tachycardia episodes and long-term ventricular tachycardia recurrences after catheter ablation. This novel methodology may represent an efficient approach in clinical practice after manual or automatic segmentation of myocardial borders in a small number of conventional 2D LGE-CMR slices and automatic scar detection., The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación and the ProCNIC Foundation (Madrid, Spain). The CNIC and the Barcelona Supercomputing Center (BSC, Barcelona, Spain) are Severo Ochoa Centers of Excellence (SEV-2015-0505 and SEV-2011-0067, respectively). This study was also supported by grants from the Fondo Europeo de Desarrollo Regional (CB16/11/00458), the Ministerio de Ciencia e Innovación (PID2019-109329RB-I00) and the Heart Rhythm Association of the Spanish Society of Cardiology (ARC). The study was also part of a Master Research Agreement between CNIC and Philips Healthcare. The study was partially supported by the Fundación Interhospitalaria para la Investigación Cardiovascular (FIC, Madrid, Spain) and the Fundación Eugenio Rodríguez Pascual (Madrid, Spain). J.A.-S. is funded by the CompBioMed2 project grant agreement 823712, H2020-EU.1.4.1.3 European Union’s Horizon 2020 research and innovation program, the SILICOFCM project, grant agreement 777204, H2020-EU.3.1.5 and by a Ramón y Cajal fellowship (RYC-2017-22532), MINECO, Spain. L.K.G was funded by the Fundación Carolina-BBVA. Grant TEC2017-82408-R is also acknowledged., Peer Reviewed, "Article signat per 25 autors/es: Susana Merino-Caviedes, Lilian K. Gutierrez, José Manuel Alfonso-Almazán, Santiago Sanz-Estébanez, Lucilio Cordero-Grande, Jorge G. Quintanilla, Javier Sánchez-González, Manuel Marina-Breysse, Carlos Galán-Arriola, Daniel Enríquez-Vázquez, Carlos Torres, Gonzalo Pizarro, Borja Ibáñez, Rafael Peinado, Jose Luis Merino, Julián Pérez-Villacastín, José Jalife, Mariña López-Yunta, Mariano Vázquez, Jazmín Aguado-Sierra, Juan José González-Ferrer, Nicasio Pérez-Castellano, Marcos Martín-Fernández, Carlos Alberola-López & David Filgueiras-Rama", Postprint (published version)

Cellulose is the most abundant organic molecule on Earth and represents a renewable and practically everlasting feedstock for the production of biofuels and chemicals. Self-assembled owing to the high-affinity cohesin-dockerin interaction, cellulosomes are huge multi-enzyme complexes with unmatched efficiency in the degradation of recalcitrant lignocellulosic substrates. The recruitment of diverse dockerin-borne enzymes into a multicohesin protein scaffold dictates the three-dimensional layout of the complex, and interestingly two alternative binding modes have been proposed. Using single-molecule fluorescence resonance energy transfer and molecular simulations on a range of cohesin-dockerin pairs, we directly detect varying distributions between these binding modes that follow a built-in cohesin-dockerin code. Surprisingly, we uncover a prolyl isomerase-modulated allosteric control mechanism, mediated by the isomerization state of a single proline residue, which regulates the distribution and kinetics of binding modes. Overall, our data provide a novel mechanistic understanding of the structural plasticity and dynamics of cellulosomes.

Advanced age significantly increases the risk of developing chronic diseases such as cancer, diabetes, cardiovascular, immune and mental disease. Regarding the latter, advanced age is a necessary factor for the development of non-hereditary forms of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Despite years of intense research, we still do not know how these diseases occur, this being one of the main reasons for the lack of adequate interventions to prevent or cure these pathologies. To overcome the current limitations in the field, we plan to: 1) generate basic knowledge on the mechanisms responsible for cognitive, behavioral, motor, metabolic and sociability disorders that occur with age, 2) define the mechanisms that determine individual susceptibility to neurodegeneration, 3) design and develop strategies to improve brain aging, and 4) explore social and environmental conditions of the older population to know their influence in brain degeneration. Individual, social and policy interventions must be considered for future research.

Venous-arterial extracorporeal membrane oxygenation (VA-ECMO) treatment for acute cardiogenic shock in patients who also have acute lung injury predisposes development of a serious complication called “north-south syndrome” (NSS) which causes cerebral hypoxia. NSS is poorly characterized and hemodynamic studies have focused on cerebral perfusion ignoring the heart. We hypothesized in NSS the heart would be more likely to receive hypoxemic blood than the brain due to the proximity of the coronary arteries to the aortic annulus. To test this, we conducted a computational fluid dynamics simulation of blood flow in a human supported by VA-ECMO. Simulations quantified the fraction of blood at each aortic branching vessel originating from residual native cardiac output versus VA-ECMO. As residual cardiac function was increased, simulations demonstrated myocardial hypoxia would develop prior to cerebral hypoxia. These results illustrate the conditions where NSS will develop and the relative cardiac function that will lead to organ-specific hypoxia., This work was supported in part by the University of Minnesota’s Medical School Academic Investment Education Program grant and the Institute for Engineering in Medicine. We also acknowledge the Partnership for Advanced Computing in Europe (PRACE) for awarding us access to Joliot-Curie Rome supercomputer at Bruyères-le-Châtel, under the project Cardiovascular-COVID. Additionally, we would like to acknowledge the Torres Quevedo Program, the Ramón y Cajal Program, and the European Institute of Innovation and Technology for support., Peer Reviewed, Postprint (published version)

Aims Develop, calibrate and evaluate with clinical data a human electromechanical modelling and simulation framework for multiscale, mechanistic investigations in healthy and post-myocardial infarction (MI) conditions, from ionic to clinical biomarkers. Methods and results Human healthy and post-MI electromechanical simulations were conducted with a novel biventricular model, calibrated and evaluated with experimental and clinical data, including torso/biventricular anatomy from clinical magnetic resonance, state-of-the-art human-based membrane kinetics, excitation–contraction and active tension models, and orthotropic electromechanical coupling. Electromechanical remodelling of the infarct/ischaemic region and the border zone were simulated for ischaemic, acute, and chronic states in a fully transmural anterior infarct and a subendocardial anterior infarct. The results were compared with clinical electrocardiogram and left ventricular ejection fraction (LVEF) data at similar states. Healthy model simulations show LVEF 63%, with 11% peak systolic wall thickening, QRS duration and QT interval of 100 ms and 330 ms. LVEF in ischaemic, acute, and chronic post-MI states were 56%, 51%, and 52%, respectively. In linking the three post-MI simulations, it was apparent that elevated resting potential due to hyperkalaemia in the infarcted region led to ST-segment elevation, while a large repolarization gradient corresponded to T-wave inversion. Mechanically, the chronic stiffening of the infarct region had the benefit of improving systolic function by reducing infarct bulging at the expense of reducing diastolic function by inhibiting inflation. Conclusion Our human-based multiscale modelling and simulation framework enables mechanistic investigations into patho-physiological electrophysiological and mechanical behaviour and can serve as testbed to guide the optimization of pharmacological and electrical therapies., This work was funded by a Wellcome Trust Fellowship in Basic Biomedical Sciences to B.R. (214290/Z/18/Z), Personalised In-Silico Cardiology (PIC) project, European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 764738, the CompBioMed 1 and 2 Centre of Excellence in Computational Biomedicine (European Commission Horizon 2020 research and innovation programme, grant agreements No. 675451 and No. 823712), an NC3Rs Infrastructure for Impact Award (NC/P001076/1), the TransQST project (Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 116030, receiving support from the European Union’s Horizon 2020 research and innovation programme and EFPIA), and the Oxford BHF Centre of Research Excellence (RE/13/1/30181). This paper is part of a supplement supported by an unrestricted grant from the Theo-Rossi di Montelera (TRM) foundation., Peer Reviewed, Postprint (published version)

Abnormal fluid dynamics at the ascending aorta may be at the origin of aortic aneurysms. This study was aimed at comparing the performance of computational fluid dynamics (CFD) and fluid-structure interaction (FSI) simulations against four-dimensional (4D) flow magnetic resonance imaging (MRI) data; and to assess the capacity of advanced fluid dynamics markers to stratify aneurysm progression risk. Eight Marfan syndrome (MFS) patients, four with stable and four with dilating aneurysms of the proximal aorta, and four healthy controls were studied. FSI and CFD simulations were performed with MRI-derived geometry, inlet velocity field and Young's modulus. Flow displacement, jet angle and maximum velocity evaluated from FSI and CFD simulations were compared to 4D flow MRI data. A dimensionless parameter, the shear stress ratio (SSR), was evaluated from FSI and CFD simulations and assessed as potential correlate of aneurysm progression. FSI simulations successfully matched MRI data regarding descending to ascending aorta flow rates (R 2 = 0.92) and pulse wave velocity (R 2 = 0.99). Compared to CFD, FSI simulations showed significantly lower percentage errors in ascending and descending aorta in flow displacement (−46% ascending, −41% descending), jet angle (−28% ascending, −50% descending) and maximum velocity (−37% ascending, −34% descending) with respect to 4D flow MRI. FSI- but not CFD-derived SSR differentiated between stable and dilating MFS patients. Fluid dynamic simulations of the thoracic aorta require fluid-solid interaction to properly reproduce complex haemodynamics. FSI- but not CFD-derived SSR could help stratifying MFS patients

Las enfermedades cardiovasculares tienen en la actualidad un gran impacto social y económico y constituyen una de las principales causas de mortalidad y morbilidad. Los modelos computacionales personalizados del corazón están demostrando ser útiles tanto para ayudar a comprender los mecanismos subyacentes a las patologías cardiacas como para optimizar su tratamiento prediciendo la respuesta del paciente. En este contexto, se ha puesto en marcha la Red Española de Investigación en Modelización Computacional Cardiaca (V-Heart SN). El objetivo general de V-Heart SN es el desarrollo de un modelo computacional multifísico y multiescala integrado del corazón. Este objetivo general se aborda a través de los siguientes objetivos específicos: a) integrar los diferentes modelos numéricos teniendo en cuenta la especificidad de los pacientes; b) ayudar a avanzar en el conocimiento de los mecanismos asociados a las diferentes patologías cardiacas y vasculares; y c) apoyar la aplicación de terapias personalizadas. Este artículo presenta el estado actual de la modelización computacional cardiaca y los diferentes trabajos científicos desarrollados por los miembros de la red para favorecer una mayor comprensión de las características y utilidad de los modelos., Postprint (author's final draft)

In this work we present a robust interface coupling algorithm called Compact Interface quasi-Newton (CIQN). It is designed for computationally intensive applications using an MPI multi-code partitioned scheme. The algorithm allows to reuse information from previous time steps, feature that has been previously proposed to accelerate convergence. Through algebraic manipulation, an efficient usage of the computational resources is achieved by: avoiding construction of dense matrices and reduce every multiplication to a matrix–vector product and reusing the computationally expensive loops. This leads to a compact version of the original quasi-Newton algorithm. Altogether with an efficient communication, in this paper we show an efficient scalability up to 4800 cores. Three examples with qualitatively different dynamics are shown to prove that the algorithm can efficiently deal with added mass instability and two-field coupled problems. We also show how reusing histories and filtering does not necessarily makes a more robust scheme and, finally, we prove the necessity of this HPC version of the algorithm. The novelty of this article lies in the HPC focused implementation of the algorithm, detailing how to fuse and combine the composing blocks to obtain an scalable MPI implementation. Such an implementation is mandatory in large scale cases, for which the contact surface cannot be stored in a single computational node, or the number of contact nodes is not negligible compared with the size of the domain., This work has been funded by CompBioMed project a grant by the EuropeanCommission H2020 (agreement nr: 823712), EUBrazilCC a project under the Programme FP7-ICT (agreement nr: 614048) and a FPI-SO grant (agreementnr: SVP-2014-068491, Peer Reviewed, Postprint (author's final draft)

High fidelity Computational Fluid Dynamics simulations are generally associated with large computing requirements, which are progressively acute with each new generation of supercomputers. However, significant research efforts are required to unlock the computing power of leading-edge systems, currently referred to as pre-Exascale systems, based on increasingly complex architectures. In this paper, we present the approach implemented in the computational mechanics code Alya. We describe in detail the parallelization strategy implemented to fully exploit the different levels of parallelism, together with a novel co-execution method for the efficient utilization of heterogeneous CPU/GPU architectures. The latter is based on a multi-code co-execution approach with a dynamic load balancing mechanism. The assessment of the performance of all the proposed strategies has been carried out for airplane simulations on the POWER9 architecture accelerated with NVIDIA Volta V100 GPUs., This work is partially supported by the BSC-IBM Deep Learning Research Agreement, under JSA \Application porting, analysis and optimization for POWER and POWER AI". It has also been partially supported by the EX-CELLERAT project funded by the European Commission's ICT activity of the H2020 Programme under grant agreement number: 823691. It has also received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number: 846139 (Exa-FireFlows). This paper expresses the opinions of the authors and not necessarily those of the European Commission. The European Commission is not liable for any use that may be made of the information contained in this paper. This work has also been nan- cially supported by the Ministerio de Economia, Industria y Competitividad, of Spain (TRA2017-88508-R). The computing experiments of this paper have been performed on the resources of the Barcelona Supercomputing Center., Peer Reviewed, Postprint (author's final draft)

This thesis aims to develop a High-Performance Computing implementation to solve large composite materials problems through the use of the FE2 multi-scale method. Previous works have not been able to scale the FE2 strategy to real size problems with mesh resolutions of more than 10K elements at the macro-scale and 100^3 elements at the micro-scale. The latter is due to the computational requirements needed to carry out these calculations. This works identifies the most computationally intensive parts of the FE2 algorithm and ports several parts of the micro-scale computations to GPUs. The cases considered assume small deformations and steady-state equilibrium conditions. The work provides a feasible parallel strategy that can be used in real engineering cases to optimize the design of composite material structures. For this, it presents a coupling scheme between the MPI multi-physics code Alya (macro-scale) and the CPU/GPU-accelerated code Micropp (micro-scale). The coupled system is designed to work on multi-GPU architectures and to exploit the GPU overloading. Also, a Multi-Zone coupling methodology combined with weighted partitioning is proposed to reduce the computational cost and to solve the load balance problem. The thesis demonstrates that the method proposed scales notably well for the target problems, especially in hybrid architectures with distributed CPU nodes and communicated with multiple GPUs. Moreover, it clarifies the advantages achieved with the CPU/GPU accelerated version respect to the pure CPU approach., Esta tesis apunta a desarrollar una implementación de alta performance computacional para resolver problemas grandes de materiales compuestos a través del método de Multi-Escala FE2. Trabajos previos no han logrado escalar la técnica FE2 a problemas de dimensiones reales con mayas de resolucion de más de 10 K elementos en la macro-escala y 100^3 elementos en la micro-escala. Esto último se debe a los requerimientos computacionales para llevar a cabo estos cálculos. Este trabajo identifica las partes computacionales más costosas del algoritmo FE2 y porta varias partes del cálculo de micro-escala a GPUs. Los casos considerados asumen condiciones de pequeñas deformaciones y estado estacionario de equilibrio. El trabajo provee una estrategía factible que puede ser usada en problemas reales de ingeniería para optimizar el diseño de estructuras de materiales compuestos. Para esto se presenta un esquema de acople entre el codigo MPI de multi-física Alya (macro-escala) y la versión acelerada CPU/GPU de Micropp (micro-escala). El sistema acoplado está diseñado para trabajar con arquitecturas de multiples GPUs y explotar la sobrecarga de GPUs. También, un método de multiple zonas de acople combinado con particionado pesado es propuesto para reducir el costo computacional y resolver el problema de balanceo de carga. La tesis demuestra que el método propuesto escala notablemente bien para los problemas modelo, especialmente en arquitecturas híbridas con nodos CPU distribuidos y comunicados con multiples GPUs. Más aún, la tesis clarifica las ventajas logradas con la versión acelerada CPU/GPU respecto a usar unicamente CPUs., Postprint (published version)

The present invention relates to a composition that comprises the peptide QBP1 for use in the inhibition of memory consolidation, after a trauma, more preferably in Post-Traumatic Stress Disorder or related diseases. [EN], Uso del péptido QBP1 para la prevención o el tratamiento del trastorno del estrés postraumático, el síndrome de estrés agudo y/o el síndrome de adaptación general. La invención se refiere a una composición que comprende el péptido QBP1 para su uso en prevenir el Trastorno de Estrés Postraumático y trastornos relacionados (como el trastorno de estrés agudo y el trastorno general de adaptación). La invención puede ser circunscrita al campo de la Medicina. [ES]

This work presents a numerical study of a technically premixed swirling combustor with central air injection at conditions close to flashback using large-eddy simulation with flamelet modelling. This burner has the characteristics of showing flashback at low equivalence ratios, so numerical simulations are set to identify the mechanisms behind the flashback formation. Experimental findings suggest the axial momentum ratio between fuel and air dominates the flame stabilization mechanism and flashback resistance over mixing and equivalence ratio fluctuations. This aspect is investigated here for two operating conditions with the same axial momentum ratio as in the experiment using a perfectly premixed assumption. The two test cases correspond to two stable operating points, far and close to the flashback point. The study shows the assumption of perfect premixing is valid during the stable operation of the burner up to flashback conditions. The experimental results are well predicted under inert and reacting conditions by using a perfectly premixed mixture. It is found that the non reacting flow field develops a self-excited oscillation in the form of a precessing vortex core. This oscillation is attenuated by the fuel injection due to the respective increase in axial momentum and it is ultimately suppressed in the reacting flow field. Both experiments and simulations confirm the same trends. The analysis of the flames have shown certain dynamics as the flashback point is approached. The flashback resistance of the burner is minimized due to an increase in the velocity deficit of the incoming mixture. The recirculation region is shifted upstream, the central recirculation is altered and the flame position is displaced towards the inlet of the reactants in the combustion chamber. The analysis of instabilities and flow dynamics suggest that the formation of flashback can be attributed to combustion induced vortex breakdown, which in turn is associated to the lower axial, The research leading to these results has received funding through the Spanish Ministry of Economy and Competitiveness in the frame of the CHEST project (TRA2017- 89139-C2-2-R). Conflict of Interest: Daniel Mira acknowledges the Juan de la Cierva personal grant IJCI-2015-26686 and Ambrus Both the Marie Skłodowska-Curie grant agreement No. 713673 through the ”la Caixa” INPhINIT Fellowship Grant. Computer resources and technical assistance has been provided by the Red Española de Supercomputación (RES) and the Gauss Centre for Supercomputing e.V. (www.gauss-centre.eu) on the GCS Supercomputer SuperMUC at Leibniz Supercomputing Centre (www.lrz.de). The TU Berlin would like to acknowledge the funding received from the EU Seventh Framework Program (FP7/2007-2013) under GA284636 and the European Research Council under the ERC GREENEST with GA247322., Peer Reviewed, Postprint (author's final draft)

Abnormal fluid dynamics at the ascending aorta may be at the origin of aortic aneurysms. This study was aimed at comparing the performance of computational fluid dynamics (CFD) and fluid–structure interaction (FSI) simulations against four-dimensional (4D) flow magnetic resonance imaging (MRI) data; and to assess the capacity of advanced fluid dynamics markers to stratify aneurysm progression risk. Eight Marfan syndrome (MFS) patients, four with stable and four with dilating aneurysms of the proximal aorta, and four healthy controls were studied. FSI and CFD simulations were performed with MRI-derived geometry, inlet velocity field and Young's modulus. Flow displacement, jet angle and maximum velocity evaluated from FSI and CFD simulations were compared to 4D flow MRI data. A dimensionless parameter, the shear stress ratio (SSR), was evaluated from FSI and CFD simulations and assessed as potential correlate of aneurysm progression. FSI simulations successfully matched MRI data regarding descending to ascending aorta flow rates (R2 = 0.92) and pulse wave velocity (R2 = 0.99). Compared to CFD, FSI simulations showed significantly lower percentage errors in ascending and descending aorta in flow displacement (−46% ascending, −41% descending), jet angle (−28% ascending, −50% descending) and maximum velocity (−37% ascending, −34% descending) with respect to 4D flow MRI. FSI- but not CFD-derived SSR differentiated between stable and dilating MFS patients. Fluid dynamic simulations of the thoracic aorta require fluid–solid interaction to properly reproduce complex haemodynamics. FSI- but not CFD-derived SSR could help stratifying MFS patients., This study was funded by Ministerio de Economía y Competitividad (grant no. RTC-2016-5152-1), Fundació la Marató de TV3 (grant no. 20151330), FP7 People: Marie-Curie Actions (grant no. 267128), Instituto de Salud Carlos III (grant nos PI14/0106 and PI17/00381) and ‘la Caixa’ Foundation. M.V. was funded by CompBioMed2, grant agreement ID: 823712, funded under: H2020-EU.1.4.1.3; and SILICOFCM, grant agreement ID: 777204, funded under: H2020-EU.3.1.5., Peer Reviewed, Postprint (published version)

The communication presents the experience developed in the last three years in a new subject organized by several professors of the Department of Structures and Building Physics (DEFE) of the Escuela Técnica Superior de Arquitectura de Madrid (ETSAM) of the Universidad Politécnica de Madrid (UPM ) in the degree in Fundamentals of Architecture. In the first semester, the degree has a compulsory experience workshop, which students must take by choosing a workshop among the offers made by each department. The experience discussed corresponds to one of the proposals by the DEFE and is called Build and Break Structures. The objective of the workshop corresponds to what is stated in the title, is that students propose a solution to a structural problem, carry out the project of that construction, build it and, finally, submit it to the expected loading situation. In the event that it exceeds the expected situation, the load continues to increase until it reaches breakage.

This work investigates the accuracy and performance of a FE2 multi-scale implementation used to predict the behavior of composite materials. The equations are formulated assuming the small deformations solid mechanics approach in non-linear material models with hardening plasticity. The uniform strain boundary conditions are applied for the macro-to-micro transitions. A parallel algorithm was implemented in order to solve large engineering problems. The scheme proposed takes advantage of the domain decomposition method at the macro-scale and the coupling between each subdomain with a micro-scale model. The precision of the method is validated with a composite material problem and scalability tests are performed for showing the efficiency., Peer Reviewed, Postprint (published version)

The main computing phases of numerical methods for solving partial differential equations are the algebraic system assembly and the iterative solver. This work focuses on the first task, in the context of a hybrid MPI+X paradigm. The matrix assembly consists of a loop over the elements, faces, edges or nodes of the MPI partitions to compute element matrices and vectors and then of their assemblies. In a MPI+X hybrid parallelism context, X has consisted traditionally of loop parallelism using OpenMP, with different techniques to avoid the race condition, but presenting efficiency or implementation drawbacks. We propose an alternative, based on task parallelism using some extensions to the OpenMP programming model. In addition, dynamic load balance will be applied, especially efficient in the presence of hybrid meshes. This paper presents the proposed methodology, its implementation and its validation through the solution of large computational mechanics problems up to 16k cores., The research leading to these results has received funding from: the European Union's Horizon 2020 Programme (2014–2020) and from Brazilian Ministry of Science, Technology and Innovation through Rede Nacional de Pesquisa (RNP), HPC4E Project, grant agreement 689772; the Energy oriented Centre of Excellence (EoCoE), grant agreement number 676629, funded within the Horizon2020 framework of the European Union; The Spanish Government (grant SEV2015-0493 of the Severo Ochoa Program); the Spanish Ministry of Science and Innovation (contract TIN2015-65316-P); the Generalitat de Catalunya (contract 2014-SGR-1051); the Intel-BSC Exascale Lab collaboration project. Comissió Interdepartamental de Recerca i Innovació Tecnológica(Interdepartmental Commission for Research and Technological Innovation), Peer Reviewed, Postprint (author's final draft)

The communication presents the experience developed in the last three years in a new subject organized by several professors of the Department of Structures and Building Physics (DEFE) of the Escuela Técnica Superior de Arquitectura de Madrid (ETSAM) of the Universidad Politécnica de Madrid (UPM ) in the degree in Fundamentals of Architecture. In the first semester, the degree has a compulsory experience workshop, which students must take by choosing a workshop among the offers made by each department. The experience discussed corresponds to one of the proposals by the DEFE and is called Build and Break Structures. The objective of the workshop corresponds to what is stated in the title, is that students propose a solution to a structural problem, carry out the project of that construction, build it and, finally, submit it to the expected loading situation. In the event that it exceeds the expected situation, the load continues to increase until it reaches breakage.

Cellulases catalyze the hydrolysis of cellulose. Improving their catalytic efficiency is a long-standing goal in biotechnology given the interest in lignocellulosic biomass decomposition. Although methods based on sequence alteration exist, improving cellulases is still a challenge. Here we show that Ancestral Sequence Reconstruction can “resurrect” efficient cellulases. This technique reconstructs enzymes from extinct organisms that lived in the harsh environments of ancient Earth. We obtain ancestral bacterial endoglucanases from the late Archean eon that efficiently work in a broad range of temperatures (30–90 °C), pH values (4–10). The oldest enzyme (~2800 million years) processes different lignocellulosic substrates, showing processive activity and doubling the activity of modern enzymes in some conditions. We solve its crystal structure to 1.45 Å which, together with molecular dynamics simulations, uncovers key features underlying its activity. This ancestral endoglucanase shows good synergy in combination with other lignocellulosic enzymes as well as when integrated into a bacterial cellulosome.

Hearing and balance rely on the transduction of mechanical stimuli arising from sound waves or head movements into electrochemical signals. This archetypal mechanoelectrical transduction process occurs in the hair-cell stereocilia of the inner ear, which experience continuous oscillations driven by undulations in the endolymph in which they are immersed. The filamentous structures called tip links, formed by an intertwined thread composed of an heterotypic complex of cadherin 23 and protocadherin 15 ectodomain dimers, connect each stereocilium to the tip of the lower sterocilium, and must maintain their integrity against continuous stimulatory deflections. By using single molecule force spectroscopy, here we demonstrate that in contrast to the case of classical cadherins, tip-link cadherins are mechanoresilient structures even at the exceptionally low Ca2+ concentration of the endolymph. We also show that the D101G deafness point mutation in cadherin 23, which affects a Ca2+ coordination site, exhibits an altered mechanical phenotype at the physiological Ca2+ concentration. Our results show a remarkable case of functional adaptation of a protein's nanomechanics to extremely low Ca2+ concentrations and pave the way to a full understanding of the mechanotransduction mechanism mediated by auditory cadherins.

Purpose: Personalized computational simulations of the heart could open up new improved approaches to diagnosis and surgery assistance systems. While it is fully recognized that myocardial fiber orientation is central for the construction of realistic computational models of cardiac electromechanics, the role of its overall architecture and connectivity remains unclear. Morphological studies show that the distribution of cardiac muscular fibers at the basal ring connects epicardium and endocardium. However, computational models simplify their distribution and disregard the basal loop. This work explores the influence in computational simulations of fiber distribution at different short-axis cuts. Methods: We have used a highly parallelized computational solver to test different fiber models of ventricular muscular connectivity. We have considered two rule-based mathematical models and an own-designed method preserving basal connectivity as observed in experimental data. Simulated cardiac functional scores (rotation, torsion and longitudinal shortening) were compared to experimental healthy ranges using generalized models (rotation) and Mahalanobis distances (shortening, torsion). Results: The probability of rotation was significantly lower for ruled-based models [95% CI (0.13, 0.20)] in comparison with experimental data [95% CI (0.23, 0.31)]. The Mahalanobis distance for experimental data was in the edge of the region enclosing 99% of the healthy population. Conclusions: Cardiac electromechanical simulations of the heart with fibers extracted from experimental data produce functional scores closer to healthy ranges than rule-based models disregarding architecture connectivity.

The aim of the present study is to characterize the hemodynamics of left ventricular (LV) geometries to examine the impact of trabeculae and papillary muscles (PMs) on blood flow using high performance computing (HPC). Five pairs of detailed and smoothed LV endocardium models were reconstructed from high-resolution magnetic resonance images (MRI) of ex-vivo human hearts. The detailed model of one LV pair is characterized only by the PMs and few big trabeculae, to represent state of art level of endocardial detail. The other four detailed models obtained include instead endocardial structures measuring ≥1 mm2 in cross-sectional area. The geometrical characterizations were done using computational fluid dynamics (CFD) simulations with rigid walls and both constant and transient flow inputs on the detailed and smoothed models for comparison. These simulations do not represent a clinical or physiological scenario, but a characterization of the interaction of endocardial structures with blood flow. Steady flow simulations were employed to quantify the pressure drop between the inlet and the outlet of the LVs and the wall shear stress (WSS). Coherent structures were analyzed using the Q-criterion for both constant and transient flow inputs. Our results show that trabeculae and PMs increase the intra-ventricular pressure drop, reduce the WSS and disrupt the dominant single vortex, usually present in the smoothed-endocardium models, generating secondary small vortices. Given that obtaining high resolution anatomical detail is challenging in-vivo, we propose that the effect of trabeculations can be incorporated into smoothed ventricular geometries by adding a porous layer along the LV endocardial wall. Results show that a porous layer of a thickness of 1.2·10−2 m with a porosity of 20 kg/m2 on the smoothed-endocardium ventricle models approximates the pressure drops, vorticities and WSS observed in the detailed models., This paper has been partially funded by CompBioMed project, under H2020-EU.1.4.1.3 European Union’s Horizon 2020 research and innovation programme, grant agreement n◦ 675451. FS is supported by a grant from Severo Ochoa (n◦ SEV-2015-0493-16-4), Spain. CB is supported by a grant from the Fundació LaMarató de TV3 (n◦ 20154031), Spain. TI and PI are supported by the Institute of Engineering in Medicine, USA, and the Lillehei Heart Institute, USA., Peer Reviewed, Postprint (published version)

This work explores the theoretical development of the virtual public sphere (EPV, as per its Spanish acronym). To respond to it, the article focuses mainly on: the genesis of the public sphere, the publications in social networks and the biographical suture, the double status of the public sphere, the tension between value in use and value in exchange, the virtual aspects of the EPV, and a brief appendix on trolls and post-truth. The EPV is an approach to interactions on the web that was developed within the framework of a PhD thesis, to study the demonstrations against the open-air mega-mining project promoted by the government of the province of La Rioja and the company Canadian Osisko Mining Corporation. This research uses the case study “Do not touch The Famatina” to review the construction of EPV., Este trabajo indaga en el desarrollo teórico de la esfera pública virtual (EPV). Para responder a ello, el artículo se enfoca en la génesis de la esfera pública, las publicaciones en las redes sociales y la sutura biográfica, el doble estatuto de lo público en la EPV, la tensión entre valores de uso y valores de cambio, qué es lo virtual de la EPV, y concluye con un acotado apéndice sobre trolls y posverdad. La EPV es un modo de abordaje de las interacciones en la web que fue desarrollado en el marco de una tesis de doctorado para estudiar las manifestaciones realizadas en 2012 contra el proyecto de megaminería a cielo abierto impulsado por la gobernación de la provincia de La Rioja, Argentina, y por la empresa canadiense Osisko Mining Corporation. Este trabajo utiliza el estudio del caso “El Famatina no se toca” para revisar la construcción de la EPV.

Study and implement a numerical code for the study of compressible flows, This report presents the study of the conservation properties for the Euler and Navier-Stokes equations ofcompressible flow, using Galerkin finite element methods. Most simulation methods for compressible flow attainnumerical stability at the cost of swamping the fine turbulent flow structures by artificial (numerical) diffusion.This study demonstrates that numerical stability can also be attained by preserving conservation laws at thediscrete level.First of all, in order to understand the Galerkin finite element methods a steady convection-diffusion trans-port problem is studied through the implementation of a Computational Fluid Dynamics (CFD) code, developedfrom scratch. Then, the numerical results of the simulations are analyzed, demonstrating that the standardGalerkin methods need stabilization techniques to avoid numerical wiggles and improve the results.Secondly, the conservation properties of Galerkin methods for the incompressible Navier-Stokes equationsare studied. A discrete formulation recently developed which conserves the energy, momentum and angularmomentum, without utilizing a strong enforcement of the divergence constraint, is shown.Finally, the compressible Euler equations and the compressible Navier-Stokes equations are studied,through the development of a second CFD code from scratch. Then, a novel discrete formulation conserv-ing energy, momentum and angular momentum is constructed for the compressible Navier-Stokes equations.Several numerical experiments are performed, which verify the theory and test the new formulation in the con-text of finite element.

Larger supercomputers allow the simulation of more complex phenomena with increased accuracy. Eventually this requires finer and thus also larger geometric discretizations. In this context, and extrapolating to the Exascale paradigm, meshing operations such as generation, deformation, adaptation/regeneration or partition/load balance, become a critical issue within the simulation workflow. In this paper we focus on mesh partitioning. In particular, we present a fast and scalable geometric partitioner based on Space Filling Curves (SFC), as an alternative to the standard graph partitioning approach. We have avoided any computing or memory bottleneck in the algorithm, while we have imposed that the solution achieved is independent (discounting rounding off errors) of the number of parallel processes used to compute it. The performance of the SFC-based partitioner presented has been demonstrated using up to 4096 CPU-cores in the Blue Waters supercomputer., The research leading to these results has received funding from the European Union Horizon 2020 Programme (2014-2020) and the Brazilian Ministry of Science, Technology and Innovation through Rede Nacional de Pesquisa (RNP) under the HPC4E Project (grant agreement No. 689772). This work is also part of the PRAC "Simulations of Aircraft Engines" supported by the National Science Foundation. It has also been financially supported by the PRACE preparatory access projects funded in part by the EU Horizon 2020 research and innovation programme (2014-2020) under grant agreement 653838. J.C. Cajas acknowledges the nancial sup- port of the `Consejo Nacional de Ciencia y Tecnolog a (CONACyT, M exico)' grant number 231588 290790. Ricard Borrell and Daniel Mira acknowledge the Juan de la Cierva postdoctoral grants with codes IJCI-2014-21034 and IJCI-2015-26686, respectively., Postprint (author's final draft)

In the field of nonlinear computational solid mechanics, contact problems deal with the deformation of separate bodies which interact when they come in touch. Usually, these problems are formulated as constrained minimization problems which may be solved using optimization techniques such as penalty method, Lagrange multipliers, Augmented Lagrangian method, etc. This classical approach is based on node connectivities between the contacting bodies. These connectivities are created through the construction of contact elements introduced for the discretization of the contact interface, which incorporate the contact constraints in the global weak form. These methods are well known and widely used in the resolution of contact problems in engineering and science. As parallel computing platforms are nowadays widely available, solving large engineering problems on high performance computers is a real possibility for any engineer or researcher. Due to the memory and compute power that contact problems require and consume, they are good candidates for parallel computation. Industrial and scientific realistic contact problems involve different physical domains and a large number of degrees of freedom, so algorithms designed to run efficiently in high performance computers are needed. Nevertheless, the parallelization of the numerical solution methods that arises from the classical optimization techniques and discretization approaches presents some drawbacks which must be considered. Mainly, for general contact cases where sliding occurs, the introduction of contact elements requires the update of the mesh graph in a fixed number of time steps. From the point of view of the domain decomposition method for parallel resolution of numerical problems this is a major drawback due to its computational expensiveness, since dynamic repartitioning must be done to redistribute the updated mesh graph to the different processors. On the other hand, some of the optimization techniques modif, En el ámbito de la mecánica de contacto computacional, los problemas de contacto tratan con la deformación que sufren cuerpos separados cuando interactúan entre ellos. Comunmente, estos problemas son formulados como problemas de minimización con restricciones, que pueden ser resueltos utilizando técnicas de optimización como la penalización, los multiplicadores de Lagrange, el Lagrangiano Aumentado, etc. Este enfoque clásico está basado en la conectividad de nodos entre los cuerpos, que se realiza a través de la construcción de los elementos de contacto que surgen de la discretización de la interfaz. Estos elementos incorporan las restricciones de contacto en forma débil. Debido al consumo de memoria y a los requerimientos de potencia de cálculo que los problemas de contacto requieren, resultan ser muy buenos candidatos para su paralelización computacional. Sin embargo, tanto la paralelización de los métodos numéricos que surgen de las técnicas clásicas de optimización como los distintos enfoques para su discretización, presentan algunas desventajas que deben ser consideradas. Por un lado, el principal problema aparece ya que en los casos más generales de la mecánica de contacto ocurre un deslizamiento entre cuerpos. Por este motivo, la introducción de los elementos de contacto vuelve necesaria una actualización del grafo de la malla cada cierto número de pasos de tiempo. Desde el punto de vista del método de descomposición de dominios utilizado en la resolución paralela de problemas numéricos, esto es una gran desventaja debidoa su coste computacional. En estos casos, un reparticionamiento dinámico debe ser realizado para redistribuir el grafo actualizado de la malla entre los diferentes procesadores. Por otro lado, algunas técnicas de optimización modifican dinámicamente el número de grados de libertad del problema al introducir multiplicadores de Lagrange como incógnitas. En este trabajo presentamos un algoritmo paralelo del tipo Dirichlet-Neumann para la resoluc, Postprint (published version)

Validated computer simulations of the airflow and particle dynamics in human nasal cavities are important for local, segmental and total deposition predictions of both inhaled toxic and therapeutic particles. Considering three, quite different subject-specific nasal airway configurations, micron-particle transport and deposition for low-to-medium flow rates have been analyzed. Of special interest was the olfactory region from which deposited drugs could readily migrate to the central nervous system for effective treatment. A secondary objective was the development of a new dimensionless group with which total particle deposition efficiency curves are very similar for all airway models, i.e., greatly reducing the impact of intersubject variability. Assuming dilute particle suspensions with inhalation flow rates ranging from 7.5 to 20 L/min, the airflow and particle-trajectory equations were solved in parallel with the in-house, multi-purpose Alya program at the Barcelona Supercomputing Center. The geometrically complex nasal airways generated intriguing airflow fields where the three subject models exhibit among them both similar as well as diverse flow structures and wall shear stress distributions, all related to the coupled particle transport and deposition. Nevertheless, with the new Stokes-Reynolds-number group, , the total deposition-efficiency curves for all three subjects and flow rates almost collapsed to a single function. However, local particle deposition efficiencies differed significantly for the three subjects when using particle diameters = 2, 10, and . Only one of the three subject-specific olfactory regions received, at relatively high values of the inertial parameter , some inhaled microspheres. Clearly, for drug delivery to the brain via the olfactory region, a new method of directional inhalation of nanoparticles would have to be implemented., The authors acknowledge Dr. Rick Corley and colleagues at Pacific Northwest National Laboratory for providing the subject B nasal surface geometry and Dr. Edgar Matida and Dr. Matthew Johnson at Carleton University for providing the subject C nasal surface geometry, Peer Reviewed, Postprint (published version)

This work explores the theoretical development of the virtual public sphere (EPV, as per its Spanish acronym). To respond to it, the article focuses mainly on: the genesis of the public sphere, the publications in social networks and the biographical suture, the double status of the public sphere, the tension between value in use and value in exchange, the virtual aspects of the EPV, and a brief appendix on trolls and post-truth. The EPV is an approach to interactions on the web that was developed within the framework of a PhD thesis, to study the demonstrations against the open-air mega-mining project promoted by the government of the province of La Rioja and the company Canadian Osisko Mining Corporation. This research uses the case study “Do not touch The Famatina” to review the construction of EPV., Este trabajo indaga en el desarrollo teórico de la esfera pública virtual (EPV). Para responder a ello, el artículo se enfoca en la génesis de la esfera pública, las publicaciones en las redes sociales y la sutura biográfica, el doble estatuto de lo público en la EPV, la tensión entre valores de uso y valores de cambio, qué es lo virtual de la EPV, y concluye con un acotado apéndice sobre trolls y posverdad. La EPV es un modo de abordaje de las interacciones en la web que fue desarrollado en el marco de una tesis de doctorado para estudiar las manifestaciones realizadas en 2012 contra el proyecto de megaminería a cielo abierto impulsado por la gobernación de la provincia de La Rioja, Argentina, y por la empresa canadiense Osisko Mining Corporation. Este trabajo utiliza el estudio del caso “El Famatina no se toca” para revisar la construcción de la EPV.

Cellulosomes are bacterial protein complexes that bind and efficiently degrade lignocellulosic substrates. These are formed by multimodular scaffolding proteins known as scaffoldins, which comprise cohesin modules capable of binding dockerin-bearing enzymes and usually a carbohydrate-binding module that anchors the system to a substrate. It has been suggested that cellulosomes bound to the bacterial cell surface might be exposed to significant mechanical forces. Accordingly, the mechanical properties of these anchored cellulosomes may be important to understand and improve cellulosome function. Here we used single-molecule force spectroscopy to study the mechanical properties of selected cohesin modules from scaffoldins of different cellulosomes. We found that cohesins located in the region connecting the cell and the substrate are more robust than those located outside these two anchoring points. This observation applies to cohesins from primary scaffoldins (i.e. those that directly bind dockerin-bearing enzymes) from different cellulosomes despite their sequence differences. Furthermore, we also found that cohesin nanomechanics (specifically, mechanostability and the position of the mechanical clamp of cohesin) are not significantly affected by other cellulosomal components, including linkers between cohesins, multiple cohesin repeats, and dockerin binding. Finally, we also found that cohesins (from both the connecting and external regions) have poor refolding efficiency but similar refolding rates, suggesting that the high mechanostability of connecting cohesins may be an evolutionarily conserved trait selected to minimize the occurrence of cohesin unfolding, which could irreversibly damage the cellulosome. We conclude that cohesin mechanostability is a major determinant of the overall mechanical stability of the cellulosome.

In this work, we present a fully coupled fluid-electro-mechanical model of a 50th percentile human heart. The model is implemented on Alya, the BSC multi-physics parallel code, capable of running efficiently in supercomputers. Blood in the cardiac cavities is modeled by the incompressible Navier-Stokes equations and an arbitrary Lagrangian-Eulerian (ALE) scheme. Electrophysiology is modeled with a monodomain scheme and the O'Hara-Rudy cell model. Solid mechanics is modeled with a total Lagrangian formulation for discrete strains using the Holzapfel-Ogden cardiac tissue material model. The three problems are simultaneously and bidirectionally coupled through an electromechanical feedback and a fluid-structure interaction scheme. In this paper, we present the scheme in detail and propose it as a computational cardiac workbench.

Intrinsically disordered proteins (IDPs) lack a tertiary structure. Amyloidogenic IDPs (aIDPs) in particular have attracted great interest due to their implication in several devastating diseases as well as in critical biological functions. However, the conformational changes that trigger amyloid formation in aIDPs are largely unknown. aIDPs' conformational polymorphism at the monomer level encumbers their study using bulk techniques. Single-molecule techniques like atomic force microscopy-based single-molecule force spectroscopy represent a promising approach and a >carrier-guest> strategy, in which the protein of interest is mechanically protected, was developed to overcome the spurious signals from the noisy proximal region. However, since the carrier and single-molecule markers have similar mechanostabilities, their signals can intermingle in the force-extension recordings, making peak selection and analysis very laborious, cumbersome and prone to error for the non-expert. Here we have developed a new carrier, the c8C module from the CipC scaffoldin, with a higher mechanostability so that the signals from the protected protein will appear at the end of the recordings. This assures an accurate, more efficient and expert-independent analysis, simplifying both the selection and analysis of the single-molecule data. Furthermore, this modular design can be integrated into any SMFS polyprotein-based vector, thus constituting a useful utensil in the growing toolbox of protein nanomechanics.

[EN] The present invention relates to a composition that comprises the peptide QBP for use in the inhibition of memory consolidation, after a trauma, more preferably in Post-Traumatic Stress Disorder or related diseases, [ES] La presente invención se refiere a una composición que comprende el péptido QBP para su uso en la inhibición de la consolidación de la memoria, después de un trauma, más preferiblemente en el trastorno por estrés postraumático o enfermedades relacionadas.

The fluid-structure interaction (FSI) problem has received great attention in the last few years, mainly because it is present in many physical systems, industrial applications, and almost every biological system. In the parallel computational field, outstanding advances have been achieved for the individual components of the problem, allowing, for instance, simulations around complex geometries at very high Reynolds numbers or simulations of the contraction of a beating heart. However, it is not an easy task to combine the advances of both fields, given that they have followed development paths in a rather independent way, and also because physical and numerical instabilities arise when dealing with two highly nonlinear partial differential equations. Nonetheless, in the last few years great advances in the coupled FSI field have been achieved, recognizing the most challenging problems to tackle and enabling a new generation of numerical simulations in aerodynamics, biological systems, and complex industrial devices. Keeping in mind that efficient parallel codes for the individual components already exist, this paper presents a framework to build a massively parallel FSI solver in a multicode coupling partitioned approach, with strong focus in the parallel implementation aspects and the parallel performance of the resulting application. The problem is casted in an algebraic form, and the main points of interest are the parallel environment needed to be able to transfer data among the codes, the location of the exchange surface, and the exchange of information among the parallel applications. The proposed framework has been implemented in the HPC multiphysics code Alya, and the multicode coupling is carried out running separated instances of this code. Two coupling algorithms with different acceleration schemes are revised, and three representative cases of different areas of interest showing the reach of the proposed framework are solved. Good agreement with litera, Postprint (published version)

Bacterial cellulases are drawing increased attention as a means to obtain plentiful chemical feedstocks and fuels from renewable lignocellulosic biomass sources. Certain bacteria deploy a large extracellular multi-protein complex, called the cellulosome, to degrade cellulose. Scaffoldin, a key non-catalytic cellulosome component, is a large protein containing a cellulose-specific carbohydrate-binding module and several cohesin modules which bind and organize the hydrolytic enzymes. Despite the importance of the structure and protein/protein interactions of the cohesin module in the cellulosome, its structure in solution has remained unknown to date. Here, we report the backbone H, C and N NMR assignments of the Cohesin module 5 from the highly stable and active cellulosome from Clostridium thermocellum. These data reveal that this module adopts a tightly packed, well folded and rigid structure in solution. Furthermore, since in scaffoldin, the cohesin modules are connected by linkers we have also characterized the conformation of a representative linker segment using NMR spectroscopy. Analysis of its chemical shift values revealed that this linker is rather stiff and tends to adopt extended conformations. This suggests that the scaffoldin linkers act to minimize interactions between cohesin modules. These results pave the way towards solution studies on cohesin/dockerin's fascinating dual-binding mode.

Bacterial cellulases are drawing increased attention as a means to obtain plentiful chemical feedstocks and fuels from renewable lignocellulosic biomass sources. Certain bacteria deploy a large extracellular multi-protein complex, called the cellulosome, to degrade cellulose. Scaffoldin, a key non-catalytic cellulosome component, is a large protein containing a cellulose-specific carbohydrate-binding module and several cohesin modules which bind and organize the hydrolytic enzymes. Despite the importance of the structure and protein/protein interactions of the cohesin module in the cellulosome, its structure in solution has remained unknown to date. Here, we report the backbone 1H, 13C and 15N NMR assignments of the Cohesin module 5 from the highly stable and active cellulosome from Clostridium thermocellum. These data reveal that this module adopts a tightly packed, well folded and rigid structure in solution. Furthermore, since in scaffoldin, the cohesin modules are connected by linkers we have also characterized the conformation of a representative linker segment using NMR spectroscopy. Analysis of its chemical shift values revealed that this linker is rather stiff and tends to adopt extended conformations. This suggests that the scaffoldin linkers act to minimize interactions between cohesin modules. These results pave the way towards solution studies on cohesin/dockerin's fascinating dual-binding mode.